Soluble sulphanilamide derivatives and process for making them



Patented not. 11, 1941 UNITED STATES PATENTOFFICE asses a DERIVATIVESsunrmmmamn am) rnocsss roa MAKING 'rnau Robert Lndovic We,Choisy-lc-Roi, Seine,-

France, anignorto Societe des Usines Chemiques Bhone-Ponlenc, Paris,France, a corporation oi France No Drawing. Application November 17,1937, SerlalNo.175,034. lnGreat Britain December Thepresent inventionrelates to the preparation oi new derivatives oi aromatic amines derivedfrom para-amino-benzene-sulphonamide. I

It is known (Goissedet et al,, Comptes Rendus Soc. 3101., 1936, Vol.121, pages 1082-1084) that it is possible to prepare products havingtherapeutic value and well suited for hypodermic in-' jection bycondensing para-amino-benzene-sulphonamide with iormaldehyde and analkalimetalbisulphite.

According to the present invention it has been found that aliphaticunsaturated aldehydes,

aromatic aldehydes, aryl-aliphatic aldehydes,

saturated or unsaturated in the aliphatic side chain, react withbisulphites and para-aminobenzene-sulphonamide, or its nuclearsubstituted derivatives to furnish new substances soluble in water andhaving great therapeutic value and well adapted ior use by hypodermicinjection. The nuclear substituted derivatives above mentioned comprisein general substituents of anot to readily reactive character and inparticular the lower alkyl nuclear derivatives; containing up to 5carbon atoms in the substituent groups, the

lower alkoxy (methoxy to amyloxy) nuclear derivatives, and the chloro,bromo, or iodo nuclear derivatives.

These compoun iormula .fi -CH-NK-AI-SOiNH:

our

- in which Rrepresents a member of the group consisting 0! an arylradical, an arslkyl radical.

a milphonated aliphatic radical and an aralkyl radical sulphonated inthe aliphatic chain and in which Ar represents an aryl radical and M represents an alkali metal. v A

In the case oi the aromatic aldehydes and arylaliphatic aldehydes havinga saturated aliphatic 40 side chain, these can be caused to reactdirectly with equal molecular quantities oi a mixture or bisulphite andoi para-amin -benaene-sulphonamide or its substituted derivatives.Equally their bisulphite caused to react in equimolecular proportionswith the amino-benzene-sulphonamide "or its derivatives. The Schiflsbases obtained-by condensation of these aldehydes withpara-aminobenzene-sulphonamide or its substituted derivas 5itivescdnalsobeusedasstarting material, these Schifls bases being thenaiterwards treated with bisulphites. A I

In the case of aldehydes presenting an unsanirated aliphatic chain, thepreparation can be st can be represented by the V derivatives can beused and- 11 Claim!- (Cl. 260-4973) carried out as above, but as thesealdehydes are capable of combining; with bisulphites at their doublebonds in the aliphatic chain, sufllcient oi the bisulphite should beused to satisfy all the possibilities of reaction with this substance.For example, it one molecular proportion of crotonic aldehyde or ofcinnamic aldehyde is used, at least two molecular proportions of sodiumbisulphite should be used.

The iollowingexamples illustrate how the invention may be carried out inpractice, but it is to be understood that the invention is in no waylimited to the details given in these examples:

"Example 1.

( a) Benzaldehydemol.) -grams- 10.6

Para-amino-benzene-sulphonamide I mol.) granis.. 17.2

2N solution of sodium bisulphite I s mol.) cc

are heated together for 2 hoursat 90 C. in a flask fitted with a stirrerand a reflux condenser.- grams of crystalline sodium acetate is thenadded. The product is filtered and allowed to cool and.crystal1ise,whereuponthe crystals are drained and washed carefully withwater andthen with alcohol. mile product is then dried and consists oibenzylamino benzene-sulphonamide-e-sulphonate of soda:

' S0 1Na This substance showed on analysis:

, v Per cent Nitrogen 7.6% theoretical. 7.69 Sulphur 17.2% theoretical17.58 Y (b) The same product is obtained by heating together in theabove manner:

Dry benzaldehyde-sodium-bisulphite 5 mol.) .'grams '21Para-amino-bensene-sulphonamide 1 (1; mol.) do 17.2 Water r 50 v Thesubsequent treatment is carried out'as in (a).

(c) The same result is obtained by starting frombenzylidene-amino-benzene-sulphonamide (melting point 204 C.) preparedby the condensation oi benzaldehyd and para-amino-benzene-sulphonamidein alcoholic solution. One

then heats in the same manner as given under '(a):

Benzylidene-amino-benzene-sulphonamide moi.) grams 26 2N solution ofsodium bisulphite (1 moi.) on 50 and the preparation continued as under(a) Example 2 Phenylacetaldehyde (1 6 mol.) grams 12Para-amino-benzene-sulphonamide are stirred in the cold in a flaskfitted with a stirrer and a reflux condenser. The contents are thenheated for half an hour at 90 C. and 63.8 grams ofamino-benzene-sulphonamide then added. The product is then filtered andallowed to crystallize, the crystals being then drained and washed witha little water and treated with alcohol, and dried-in a vacuum. There isthus obtained a white, crystalline product which is para-['y-phenyl-propylamino] -benzenesulphonamide-a-y-disulphonate of soda:

SOsNa SOrNB CeHr- H 'CHQ(EHNH COHA-SOQNHJ Found by analysis Per centNitrogen, 5.57% theoreticaL 5.66 Sulphur, 19% theoretical 19.4

(b) The same product is obtained by mixing and heating at the start thethree constituents, namely, sodium bisulphite, cinnamic aldehyde andamino-benzene-sulphonamide,

(0) By starting with the Schifi's base having a melting point of 240 0.prepared from cinnamic aldehyde and phonamine in alcohol, obtained.

moi. proportion of cinnamylidene-aminothe same product can bebenzene-sulphonamide grams 14.3-

1 mol. proportion of sodium bisulphite solution (N) cc 100 are heated at90 C. for 2 hours and treated as above.

Example 4 The cinnamic aldehyde in Example 3 can bepara-amino-benzene-sulreplaced by the equivalent molecular quantity ofacrylic aldehyde or crotonic aldehyde and there are then obtained thecompounds having the formulae:

some some m-cm-on-nn-cm-somm and SOaNa SOnNs OH H-CHr H-NH-CaHr-SOsNH:

respectively.

What I claim and Patent is:

1. The water-soluble therapeutically active compound desire to secure byLetters 3. The water-soluble therapeutically active compound SOHNE some4. Process for preparing water-soluble compounds of therapeutical value,which consists in stirring at ordinary temperature a phenyl lowermono-unsaturated aliphatic aldehyde with at least two molecularproportions of an alkali metal bisulphite, and heating the resultingmixture with p-amino-benzene-sulphonamide.

5. Process for preparing water-soluble compounds of therapeutical value,which consists in stirring at ordinary temperature a'lowermonounsaturated-aliphatic aldehyde with at least two molecularproportions of an alkali metal bisulphite, and heating the resultingmixture with p-amino-benzene-sulphonamide.

6. Process for preparing water-soluble compounds of therapeutical value,which consists in stirring an aldehyde of the group consisting ofbenzaldehyde, the phenyl lower aliphatic aldehydes saturated in the'sidechain, the phenyl lower aliphatic aldehydes mono-unsaturated in the sidechain, and the lower mono-unsaturated aliphatic aldehydes with an alkalimetal bisulphite to form a bisulphite compound, and then heating theresulting bisulphite compound with p-amino-benzene-sulphonamide.

7. Process for preparing water-soluble compounds of therapeutical value,which consists in condensing in alcohol an aldehyde 0! the groupconsisting of benzaldehyde, the phenyl lower aliphatic aldehydessaturated in phenyl lower aliphatic aldehydes mono-unsaturated in theside chain and the lower monounsaturated aliphatic aldehydes, withp-aminobenzene-sulphonamide to form a Schifl's base,

which is then heated with a solution 01' alkali metal'bisulphite.

8. Process for preparing water-soluble compounds of therapeutical value,which consists in heating an aldehyde of the group consisting ofbenzaldehyde, the phenyl lower aliphatic aldehydes saturated in the sidechain, the phenyl lower aliphatic aldehydes mono-unsaturated in the sidechain,' and the lower mono-unsaturated aliphatic aldehydes withp-amino-benzene-sulphonamide and a solution of an alkali metalbisulphite.

9. Process for preparing water-soluble compounds of therapeutical value,which consists in heating a phenyl lower aliphatic aldehyde withp-amino-benzene-sulphonamide and a solution of an alkali metalbisulphite.

10. The water-soluble therapeutically valuable compounds represented bythe formula in which R represents a member of the group consisting 01' aphenyl radical, a benzyl radical, a lower aliphatic radical and the sidechain, the.

2,202,544 3 a phenyl lower aliphatic radical, sulphonated on theultimate condensation of these reagents,

the side chain, of the type I whereby are formed compoimds representedby CHPCIFCHP I the formula OsM 5 I 0M and in which Ar represents abenzenoid radical,

and M represents an alkali metalconsisting of a phenyl radical, a benzylradical,

Process for preparing water'soluble a sulphonated saturated loweraliphatic radical pounds of therapeutical value, which consists in and aphenyl lower aliphatic radical l h t d treatingp-amino-benzene-sulphonamide and an 10 on the side chain, of the typealkali metal bisulphit'e with an aldehyde 0! the group consisting ofbenzaldehyde, the phenyl lower aliphatic aldehydes saturated in the side0M chain, the phenyl lower aliphatic aldehydes mono- Y and in which Arrepresents a benzenoid radical,

unsaturated in the sideflchain, and the'lower 15andMrepresentsanalkallmetal.

mono-unsaturated aliphatic aldehydes to effect ROBERT LUDOVIC DESPOIS.

in which R represents a member of the group"

